While there are many patents and publications available which relate to the transdermal administration of steroid drugs, and the use of penetration enhancer, the applicant is unaware of any prior art which relates to the enhancer and vehicle composition of a semisolid dosage form disclosed herein and to use such composition in the transdermal administration of estrogen, progestin or a mixture thereof.
The present invention relates to a novel composition based on enhancers combination in a vehicle composite for transdermal administration of steroid hormones alone or mixture thereof. A formulation that provides therapeutically useful concentrations of steroid hormones such as estradiol and norethindrone for hormone replacement therapy.
When the ovaries do not function properly due to age i.e. menopause or disease or have been removed, the consequent lack of endogenous estradiol may produce a number of symptoms, such as hot flushes, pain and increased hypocalcemia which may eventually lead to osteoporosis.
One possibility of avoiding or alleviating these symptoms is by hormone replacement therapy i.e. by prescribing a compensatory doses of estrogen to the patient.
The serum levels of estradiol required for clinical efficacy have been reviewed by Powers between 40-60 pg/ml. This range of values are the physiologic serum levels of the premenopausal women during the early follicular phase.
Various methods or dosage forms are in use or have been proposed for the estradiol replacement therapy e.g. tablets, injectable, implants and transdermal devices (patches or gel) etc.
Oral therapy, using tablets is well accepted by the patient. However estradiol is rapidly metabolized during the liver first pass inactivation generating estrone. Thus, a high dose of estradiol is necessary to achieve clinical appropriate estradiol serum levels and as a consequence, high estrone serum levels are produced above physiological values. Absorption via the gastrointestinal tract results in enhanced delivery of the circulating estrogen to the liver, where much of it is metabolized to inactive conjugates, and only a fraction of the active hormone enter general circulation. The liver responds to this enhanced delivery with increased protein and lipid metabolism, and these activities may carry potential risks.
Examples of these changes include enhanced hepatic synthesis of renin substrates, sex hormone-binding globulin, and changes in cholesterol and lipid lipoprotein metabolism.
The use of parenteral injections and implants or pellets while avoiding the first pass metabolization is much less convenient for the patient, then these dosage forms are not popular.
The estradiol transdermal administration is the cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate. Clinical studies shows beneficial effects of transdermal estradiol on plasma. Gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood attention) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogen on hepatic metabolism are avoided (Balfour 1990).
The physicians normally prescribe a progestin combining estrogen to postmenopausal women who have not undergone hysterectomy. Unopposed estrogen cause endometrial hyperstimulation, which lead to irregular vaginal bleeding, endometrial hyperplasia and cancer. Only progestin addition can protect the endometrium while maintaining the beneficial effects of estrogen on symptoms and the skeleton. According to the literature, the transdermal dose of norethindrone acetate required to oppose estrogen hyperstimulation of the endometrium is about 200-300 mcg/day (Whitehead 1990).
Transdermal estradiol must be administered continuously or in 28 day cycle, consisting of three weeks treatment followed by a one week treatment free interval (during which vaginal bleeding may occur). Continuous therapy may be particularly suitable for women who have undergone hysterectomy or those symptoms of estrogen deficiency occur during free intervals.
Additional progestin treatment should be taken by patients with an intact uterus for 10 to 15 consecutive days of each month. Withdrawal bleeding will usually occur at the end of each phase of progestin therapy whether estrogen treatment is cyclical or continuous.
Continuous/combined therapy (continuous estrogen with continuous progestin) has the advantage of not causing withdrawal bleeding.
Transdermal administration of drugs offers several therapeutic and compliance advantages over the more traditional routes of administration. A major drawback of this therapy however, is the limitation of the amount of drug that can be transported across the skin. This limitation is due to several factors. Since the skin is a protective barrier by nature, the rates of transport of most compounds through the skin is quite slow. It is generally accepted that a surface of patch beyond 50-100 sqcm would result in difficulty of application. Therefore the application of a transdermal semisolid dosage form such as a gel, cream, ointment, liquid, etc., augment the patient's compliance and the surface of application can be extended.
In order to overcome the barrier properties of the stratum corneum and facilitate the percutaneous absorption of the active agent, many compounds are described as penetration enhancer, such as, azone, glycol, pyrrolidone, fatty alcohol, fatty acid and ester thereof, etc., mentioned by M.o slashed.llgaard in "Pharmaceutical Skin Penetration Enhancement", Marcel Dekker, New York 1993, pages 229-242.
EPA 0 367 431 discloses that aliphatic alcohols such as isopropyl alcohol and isobutyl alcohol that are commonly used in topical transdermal formulation thus, enhance the rate of transdermal delivery of steroid drugs.
EP 0 573 133 claims a transdermal device which contains gestodem in combination with one or more estrogens. It is also described the addition of transdermal penetration enhancers.
FR 2 518 879 claims a medicament based of estradiol for postmenopausal treatment. This simple medicament is an hydroalcoholic gel where estradiol is dissolved in the above mentioned vehicles and is appointed to administer estradiol by transdermal route.
EPA 0 279 977 describes a transdermal device for administering progesterone and an estradiol ester alone or in combination, utilizing a polymer matrix which has the drug(s) with a penetration enhancer such as sucrose monococoate, glycerol monooleate, sucrose monolaurate, glycerol mnolaureate, etc.
U.S. Pat. No. 5,023,084 claims a transdermal estrogen/progestin device comprising a polymeric layer made from polymer adhesive such as polyacrylic, silicone or other suitable polymer adhesives and decyl alcohol as penetration enhancer.
GB 2 208 147 A discloses a transdermal reservoir type with controlled membrane for the administration of estrogen and progestin, containing ethanol as an agent that enhances the percutaneous absorption.
WO 90/11 064 discloses a skin penetration enhancer composition for estrogen and progestin or a mixture thereof. The composition contains diethylene glycol monoethyl or monomethyl ether in addition to propylene glycol monolaurate, methyl laurate or the like.
None of the above mentioned inventions or publications report a study of lauryl alcohol together with diethylene glycol monoethyl ether in a ternary vehicle composite in a semisolid dosage form, designed to administer estradiol and norethindrone acetate simultaneously by the transdermal route.
One object of the present invention is to obtain a transdermal formulation that could deliver, at controlled rates, both an estrogen and progestin combined with appropriate permeation enhancers. This is very important since it is well known that transdermal permeability is mainly influenced by both physicochemical properties of the permeants and by the interaction of the permeants with the enhancers. Therefore a given enhancer could prove to be very adequate for an hormone and simultaneously would not increase the permeability of the other hormone. This is well illustrated by Chien, in its chapter on "Development Concepts and Practice in Transdermal Therapeutic Systems" in Transdermal Therapeutic Systemic Medications, Marcel Dekker Inc., New York, 1987, pages 25-81, who state that a penetration enhancer increases the permeation of different compound to different degree.
There has not been known an enhancer or combination thereof which shows the transdermal penetration enhancement effect for any active agent or drug. As an example we can quote results of this author as therein below indicated:
______________________________________ Enhancement of Skin Permeability of Various Drugs by Different Types of Enhancer Enhancement factor.sup.a Propyl Propyl Decylmethyl Drugs myristate oleate Azone sulfoxide ______________________________________ Progesterone 4.56 5.36 5.96 11.04 Estradiol 9.33 14.62 20.17 12.59 Hydrocortisone 4.57 5.01 61.3 25.23 Indomethacin 3.77 4.67 14.49 15.67 ______________________________________ .sup.a Enhancement factor = (Normalized skin permeation rate) with enhancer/(Normalized skin permeation rate) without enhancer.
Additionally, another argument in favor of our position is sustained when the results reported by Chien are analyzed. He published the dependence of the enhancement factor for the skin permeation of progesterone on the alkyl chain length of saturated fatty acid in "Transdermal Therapeutic Systemic Medications". He found the major enhancement effect using caproic acid (C8), however the same author discloses in U.S. Pat. No. 5,145,682 that the better enhancer for estradiol is decanoic acid (C10) . These results lead us to attain the same conclusion of Chien in "Transdermal Controlled Systemic Medications", Marcel Dekker, New York 1987, pages 25-81, that concludes that the efficacy of skin penetration enhancer for a specific active agent, is function of the type, concentration and, how the penetration enhancer release from the devices.
The prior art presented herein clearly prove that at least for steroid compounds, as shown in the present patent application, there is no such an universal penetration enhancer composition and the adequate permeation rate across the skin can be achieved only by testing different types of compounds at different concentrations. Although prior art was useful for the theoretical approach, the results emerged from the careful investigation of multiple variables.